Stabilization of nuclear β-catenin by inhibiting KDM2A mediates cerebral ischemic tolerance.

Hypoxic postconditioning (HPC) with 8% oxygen increases nuclear accumulation of β-catenin through activating the classical Wnt pathway, thereby alleviating transient global cerebral ischemia (tGCI)-induced neuronal damage in the hippocampal CA1 subregion of adult rats. However, little is understood about the regulatory mechanism of nuclear β-catenin in HPC-mediated cerebral ischemic tolerance. Although lysine(K)-specific demethylase 2A (KDM2A) has been known as a crucial regulator of nuclear β-catenin destabilization, whether it plays an important role through modulating nuclear β-catenin in cerebral ischemic tolerance induced by HPC remains unknown. In this study, we explored the molecular mechanism of stabilizing nuclear β-catenin by inhibiting KDM2A-mediated demethylation in the HPC-offered neuroprotection against tGCI. In addition, we confirmed that nuclear methylated-β-catenin in CA1 decreased and nuclear β-catenin turnover increased after tGCI, which were reversed by HPC. The administration with methyltransferase inhibitor AdOx abrogated HPC-induced methylation and stabilization of nuclear β-catenin in CA1, as well as the neuroprotection against tGCI. Notably, HPC downregulated the expression of KDM2A in CA1 and reduced the interaction between KDM2A and β-catenin in the nucleus after tGCI. The knockdown of KDM2A with small-interfering RNA could upregulate nuclear methylated-β-catenin and stabilize β-catenin, thereby increasing survivin in CA1 and improving the cognitive function of rats after tGCI. Opposite results were observed by the administration of KDM2A-carried adenovirus vector. Furthermore, we demonstrated that KDM2A mediates the demethylation of nuclear β-catenin through jumonji C (JmjC) domain of KDM2A in HEK-293T and SH-SY5Y cells. Our data support that the inhibition of KDM2A-mediated demethylation of nuclear β-catenin contributes to HPC-induced neuroprotection against tGCI.